The project #2 constitutes one of the three scientific research proposals of this TMRC that focus on zoonotic cutaneous leishmaniasis (ZCL) due to Leishmania (L.) major. The disease is highly prevalent in North Africa, the Middle East and Central Asia. The long-term goal of this proposal (Project #2) is to elucidate the immunological mechanisms operating for resistance against the parasite as a prerequisite to the development of vaccine against this disease. The specific hypothesis is that both parasite antigens and sand fly saliva molecules could contribute to the induction of immune response and protection. Our main objective is to identify the immune correlates of protection and to compare the immunogenicity of a set of selected proteins of parasite or sand fly origin that might constitute potential candidate vaccines. This will be done using prospective study of L. major infection analyzing the effects of host factors (tested at the baseline of the cohort follow-up) on the resistance against infection, disease occurrence or recurrence. The specific Aims are: 1- To identify Leishmania-spectf\c effective immunological mechanisms operating for resistance against human L. major infection. This will be done by the analysis of indicators of innate or adaptive (memory) cellular response against the parasite and their eventual correlation with resistance against ZCL. The study will comprise a cohort of exposed individuals living in endemic area of L. mayortransmission (see Project #1). 2- To compare the antigenicity of a set of selected proteins of parasite origin by analysing the type and the intensity of the specific cellular immune response that they induce and its eventual correlation with resistance. 3- To determine if people exposed to phlebotomine sand fly bites develop detectable antibodies and cellular immune response to the vector's saliva, and if so, if there is any association with the clinical expression of Leishmania infection. The antigenicity of a set of ~ 15 saliva antigens of vector origin will be comparatively analyzed.